Entrenchment and contingency in neutral protein evolution with epistasis

Area of Science:

• Evolutionary biology
• Molecular evolution
• Computational biology

Background:

• Epistasis, where gene interactions affect fitness, complicates protein sequence evolution.
• Entrenchment describes how amino acid sites become less tolerant to change over time, even with neutral substitutions.
• Existing models, like Potts Hamiltonian, often simulate non-neutral protein evolution despite aiming for neutral scenarios.

Purpose of the Study:

• To introduce and test a new model, Neutral-with-Epistasis (N×E), that integrates purifying selection into neutral evolution simulations.
• To investigate the phenomenon of entrenchment in protein evolution under simulated neutral conditions with epistasis.
• To clarify the drivers of molecular clock overdispersion and their relationship to epistasis and evolutionary processes.

Main Methods:

• Development of the Neutral-with-Epistasis (N×E) model incorporating purifying selection.
• Simulations of protein evolution using the N×E model to observe amino acid site dynamics.
• Analysis of molecular clock variation and its correlation with site-specific epistasis.

Main Results:

• The N×E model demonstrated a lack of entrenchment, with conserved site-specific amino acid preferences over biologically realistic timescales.
• Extensive residue coupling did not lead to the expected loss of site-specific preferences.
• Molecular clock overdispersion was attributed to site-specific rate variation driven by epistasis within lineages, not historical contingency.

Conclusions:

• Neutral evolution models need to incorporate purifying selection to accurately simulate protein sequence dynamics and avoid apparent entrenchment.
• Epistasis, when coupled with purifying selection, maintains site-specific amino acid preferences, challenging previous assumptions about entrenchment.
• The findings suggest that observed substitutional entrenchment and rate contingency may be indicators of non-neutral evolutionary forces, such as adaptation.